ABSTRACT Sepsis-induced ALI/ARDS is a devastating syndrome of acute respiratory failure in critically ill patients that accounts for among the highest admission rates in ICU and mortality. During STTR Phase I, we at Cell Biologics Inc., demonstrated that piceatannol, a naturally occurring anti-inflammatory that selectively inhibits Syk tyrosine kinase, when entrapped in 150 nm albumin nanoparticles (PANPs) was therapeutically effective in treating experimental ALI and significantly reduced mortality in 3 different mouse sepsis induced ALI/ARDS models such as endotoxemia, cecal ligation puncture (CLP)-induced polymicrobial sepsis, and pneumonia induced by Pseudomonas aeruginosa. This protection was ascribed to direct PANP-mediated delivery of the drug into phagocytic cells and could not be reproduced by injecting the inhibitor alone. Moreover, albumin nanoparticles (ANP), without the drug entrapped, had no therapeutic effect. The nanoparticles were preferentially taken up by cell surface Fc?RIIIa expressed in activated phagocytic cells such as neutrophils and monocytes/macrophages. Treatment with PANPs suppressed the IL-I??and TNF? inflammatory cytokine storm. Importantly, PANP treatment however did not adversely affect the host defense response in circulating non-adherent phagocytic cells. In normal mice, PANPs were mainly internalized by liver cells whereas they were preferentially in lung microvascular entrapped activated phagocytic cells in endotoxemic mice model substantiating our hypothesis that PANPs target activated phagocytic cells mediating ALI/ARDS. The overreaching goal in STTR Phase II is to generate supporting data to seek FDA ?IND? status for PANP therapy of ALI/ARDS. For Phase II, we chose Pig and ex vivo human lung models of sepsis induced ALI/ARDS, as these are the closest to humans. In specific aim 1, we will undertake the scaling-up of PANPs to meet demands of pig sepsis-induced ALI/ARDS and ex vivo human lung studies. We will ensure stability, potency and storage capabilities of the nanoparticles. Specific aim 2 will determine pharmacokinetic parameters, drug metabolism and early toxicological studies using the pig model. The goal of specific aim 3 will be to establish the efficacy of PANPs in treatment of sepsis-induced ALI/ARDS. As the disease has multiple etiologies, studies in pigs will be made using LPS (endotoxemia), E. coli-induced peritonitis, and polymicrobial sepsis induced by CLP. Studies in the ex vivo human lung model will be made by challenging lungs with bacterial pneumonia (E. coli) delivered by the intra-tracheal route. We will concomitantly implement the detailed commercialization plan we have developed with the help of bio-pharma industry, FDA and clinical consultants. We have established clear time lines of goals to be achieved for submission of IND package to FDA. In addition, we have outlined the necessary regulatory pathway. We have also proposed a PANP based patient intervention plan that will aid us in pursuing future PANP clinical trials. As we make progress validating the efficacy of PANP in pig and ex vivo human lung models of ALI, we will make aggressive efforts to seek commitments from biopharma and investment firms.